Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. significant effect on amprenavir AUCss (= 0.004) and = 0.015). This pharmacokinetic evaluation of amprenavir-containing dual protease inhibitor regimens compared amprenavir steady-state pharmacokinetics calculated from subjects receiving amprenavir monotherapy with those from subjects receiving amprenavir in combination with another protease inhibitor. Historical monotherapy data for indinavir, nelfinavir, and saquinavir sgc were used as reference values for the steady-state pharmacokinetics of the partner protease inhibitor in each combination. The concurrent study design employed was used to avoid unnecessarily exposing subjects to protease inhibitor monotherapy (i.e., by a crossover design) which could potentially facilitate the development of drug resistance. Amprenavir is approved as a twice-daily regimen, but given the three-times-a-day dosing schedule of the partner protease inhibitors, amprenavir was instructed to be taken three times daily in this study to simplify logistics and for the convenience of Anacardic Acid the participants. To characterize any drug-drug interactions after multiple dosing, steady-state pharmacokinetic data for the individual protease inhibitors in each of the dual protease inhibitor combinations were compared with the steady-state data for each protease inhibitor given alone. The decrease in amprenavir AUCss that occurred when amprenavir was coadministered with saquinavir sgc may prove to be clinically relevant. Several studies of HIV protease inhibitors have shown that AUCss and = 11) and nonblacks (= 23). Gender was not evaluated because two treatment groups had only one female each. The finding of a significant treatment effect by the partner protease inhibitor indicates that each of the protease inhibitors had different effects on amprenavir steady-state pharmacokinetics. AAG concentrations were significantly correlated with amprenavir steady-state pharmacokinetics. Decreasing AAG concentrations, as would occur with suppressive HIV therapy, were associated with decreasing total concentrations of amprenavir (i.e., protein-bound and unbound drug). Like most HIV protease inhibitors, amprenavir exhibits a high degree of high-affinity binding to AAG (90%) (12). Changes in AAG, Anacardic Acid while affecting the measured total amprenavir concentration, are not believed to Anacardic Acid affect the unbound amprenavir concentration, since clearance of unbound drug (i.e., intrinsic clearance) is unchanged (20). The present study was designed to evaluate the pharmacokinetics and short-term safety of multiple-dose, dual protease inhibitor therapy in protease inhibitor-na?ve, HIV-infected subjects. Steady-state pharmacokinetic data for all four protease inhibitors in the three dual protease inhibitor combinations obtained in this research reveal that no medication interactions preclude Anacardic Acid the usage of the mixtures and claim that additional investigation from the dual protease inhibitor regimens as an antiretroviral therapy technique can be warranted. The outcomes of this research have supported continuing treatment of the topics in the stage I-II follow-on of the research to judge longer-term protection and efficacy from the amprenavir-containing dual HIV protease inhibitor regimens. Acknowledgments We say thanks to Cindy Rawls for bioanalytical evaluation of amprenavir; David Morris for bioanalytical evaluation of indinavir, nelfinavir, and saquinavir; Elegance Janet and Pagano Green for clinical monitoring; as well as the scholarly Anacardic Acid research topics for his or her involvement. We thank DES Merck & Co also., Agouron Pharmaceuticals, Inc., and Roche Laboratories for providing research drugs. This scholarly study was sponsored with a grant from Glaxo Wellcome Inc. Referrals 1. Barry M, Gibbons S, Back again D, Mulcahy F. Protease inhibitors in individuals with HIV disease. Important pharmacokinetic considerations Clinically. Clin Pharmacokinet. 1997;32:194C209. [PubMed] [Google Scholar] 2. Cameron W, Heath-Chiozzi M, Danner S, Cohen C, Kravcik S, Maurath C, Sunlight E, Henry D, Rode R, Potthoff A, Leonard J for the Advanced HIV Disease Ritonavir Research Group. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. Lancet. 1998;351:543C549. [PubMed] [Google Scholar] 3. Carpenter C, Cooper D, Fischl M, Gatell J, Gazzard B, Hammer S, Hirsch M, Jacobsen D, Katzenstein D, Montaner J, Richman D, Saag M, Schechter M, Schooley R, Thompson M, Vella S, Yeni P, Volberding P. Antiretroviral therapy in adults. Up to date.